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1.
Br J Clin Pharmacol ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33444472

RESUMO

AIM: Clofarabine has recently been evaluated as part of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HCT) in children. Pharmacokinetic (PK) exposure of different agents commonly used in conditioning regimens is strongly related to HCT outcome. Consequently, the PK of clofarabine may be important for outcome. This report describes the population PK of clofarabine in pediatric patients and one adult. METHODS: From 80 pediatric (0.5-18 years) and 1 adult patient (37 years), 805 plasma concentrations were included in pharmacokinetic analyses using non-linear mixed effects modelling. RESULTS: A two-compartment model adequately described the PK of clofarabine. Body weight and estimated glomerular filtration rate (eGFR) were included as covariates. Clearance was differentiated into non-renal and renal clearance (approximately 55% of total clearance), resulting in population estimates of 24.0 L/h (95% confidence interval (CI) 13.7-34.4) and 29.8 L/h (95% CI 23.9-36.1) for a patient of 70 kg with normal renal function, respectively. Unexplained interindividual variability in clearance was 17.8% (95% CI 14.6%-22.4%). A high variability in exposure was observed (range area under the curveT0-inf 1.8-6.0 mg/L*h) after body surface area (BSA) based dosing. Interestingly, children with low body weight had a lower exposure than children with a higher body weight, which indicates that the currently practiced BSA based dosing is not adequate for clofarabine. CONCLUSION: A clofarabine dosing algorithm based on this PK model, using body weight and eGFR, results in a more predictable exposure than BSA based dosing. However, the exact target exposure needs to be further investigated.

2.
Front Microbiol ; 11: 560179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281758

RESUMO

Pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients often suffer from gastro-intestinal (GI) disease caused by viruses, Graft-versus-Host Disease (GVHD) or a combination of the two. Currently, the GI eukaryotic virome of HSCT recipients remains relatively understudied, which complicates the understanding of its role in GVHD pathogenicity. As decisions regarding immunosuppressive therapy in the treatment of virus infection or GVHD, respectively, can be completely contradicting, it is crucial to better understand the prevalence and relevance of viruses in the GI tract in the HSCT setting. A real time PCR panel for a set of specific viruses widely used to diagnose the most common causes of GI viral gastroenteritis is possibly insufficient to grasp the full extent of viruses present. Therefore, we applied the targeted sequence capture method ViroCap to residual fecal samples of 11 pediatric allogeneic HSCT recipients with GI symptoms and a suspicion of GVHD, to enrich for nucleic acids of viruses that are known to infect vertebrate hosts. After enrichment, NGS was applied to broadly detect viral sequences. Using ViroCap, we were able to detect viruses such as norovirus and adenovirus (ADV), that had been previously detected using clinical diagnostic PCR on the same sample. In addition, multiple, some of which clinically relevant viruses were detected, including ADV, human rhinovirus (HRV) and BK polyomavirus (BKV). Interestingly, in samples in which specific PCR testing for regular viral GI pathogens did not result in a diagnosis, the ViroCap pipeline led to the detection of viral sequences of human herpesvirus (HHV)-7, BKV, HRV, KI polyomavirus and astrovirus. The latter was an only recently described variant and showed extensive sequence mismatches with the applied real time PCR primers and would therefore not have been detected if tested. Our results indicate that target enrichment of viral nucleic acids through ViroCap leads to sensitive and broad possibly clinically relevant virus detection, including the detection of newer variants in clinical HSCT recipient samples. As such, ViroCap could be a useful detection tool clinically, but also in studying the associations between viral presence and GVHD.

3.
Blood ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33150379

RESUMO

Acute Graft-versus-Host-Disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell reconstitution (CD4+IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients who developed aGvHD. Pediatric patients receiving their first allogeneic HCT at the UMC Utrecht / Princess Máxima Center (UMC/PMC) or Memorial Sloan Kettering Cancer Center (MSK), were included. Primary outcomes were non-relapse mortality (NRM) and overall survival (OS), stratified for aGvHD and CD4+IR; defined as ³50 CD4+ T-cells/uL within 100 days after HCT, or prior to aGvHD onset. Multivariate and time-to-event Cox Proportional Hazard models were applied. 591 Patients (N= 276 UMC/PMC; N= 315 MSK) were included. NRM in patients with aGvHD grade III-IV with or without CD4+IR within 100 days after HCT was 30% vs 80% (p=0.02) at UMC/PMC and 5% vs 67% (p=0.02) at MSK. This associated with lower OS without CD4+IR; 61% vs. 20% (p=0.04) at UMC/PMC, and 75% vs. 33% (p=0.12) at MSK. Inadequate CD4+IR prior to aGvHD onset associates with significantly higher NRM; 74% vs 12% (p<0.001), and inferior OS; 24% vs 78% (p<0.001). In this retrospective analysis we demonstratethat early CD4+ IR, a simple and robust markerpredictive of outcomes after HCT,associates with survival after moderate to severe aGvHD.These associations need to be confirmed in a prospective manner but suggest that strategies to improve T-cell recovery after HCT may influence survival in patients developing aGvHD.

4.
Front Immunol ; 11: 559152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101274

RESUMO

Hematopoietic cell transplantation (HCT) is a last resort, potentially curative treatment option for pediatric patients with refractory acute myeloid leukemia (AML). Cord blood transplantation (CBT) results in less relapses and less graft-versus-host disease when compared to other sources. Nevertheless, still more than half of the children die from relapses. We therefore designed a strategy to prevent relapses by inducing anti-AML immunity after CBT, using a CB-derived dendritic cell (CBDC) vaccine generated from CD34+ CB cells from the same graft. We here describe the optimization and validation of good manufacturing practice (GMP)-grade production of the CBDC vaccine. We show the feasibility of expanding low amounts of CD34+ cells in a closed bag system to sufficient DCs per patient for at least three rounds of vaccinations. The CBDCs showed upregulated costimulatory molecules after maturation and showed enhanced CCR7-dependent migration toward CCL19 in a trans-well migrations assay. CBDCs expressed Wilms' tumor 1 (WT1) protein after electroporation with WT1-mRNA, but were not as potent as CBDCs loaded with synthetic long peptides (peptivator). The WT1-peptivator loaded CBDCs were able to stimulate T-cells both in a mixed lymphocyte reaction as well as in an antigen-specific (autologous) setting. The autologous stimulated T-cells lysed not only the WT1+ cell line, but most importantly, also primary pediatric AML cells. Altogether, we provide a GMP-protocol of a highly mature CBDC vaccine, loaded with WT1 peptivator and able to stimulate autologous T-cells in an antigen-specific manner. Finally, these T-cells lysed primary pediatric AML demonstrating the competence of the CBDC vaccine strategy.

5.
Blood ; 136(10): 1201-1211, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32614953

RESUMO

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

6.
Blood Adv ; 4(12): 2837-2849, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32574368

RESUMO

Mucopolysaccharidoses (MPSs) are multiorgan devastating diseases for which hematopoietic cell transplantation (HCT) and, to a lesser extent, enzyme replacement therapy have substantially altered the course of the disease. Furthermore, they have resulted in increased overall survival, especially for Hurler disease (MPS-1). However, despite the identification of clinical predictors and harmonized transplantation protocols, disease progression still poses a significant burden to patients, although at a slower pace. To design better therapies, we need to understand why and where current therapies fail. In this review, we discuss important aspects of the underlying disease and the disease progression. We note that the majority of progressive symptoms that occur in "hard-to-treat" tissues are actually tissues that are difficult to reach, such as avascular connective tissue or tissues isolated from the circulation by a specific barrier (eg, blood-brain barrier, blood-retina barrier). Although easily reached tissues are effectively cured by HCT, disease progression is observed in these "hard-to-reach" tissues. We used these insights to critically appraise ongoing experimental endeavors with regard to their potential to overcome the encountered hurdles and improve long-term clinical outcomes in MPS patients treated with HCT.

7.
JAMA Netw Open ; 3(1): e1918668, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31913492

RESUMO

Importance: Patients undergoing hematopoietic stem cell transplant (HSCT) are at risk for bloodstream infection (BSI) secondary to translocation of bacteria through the injured mucosa, termed mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI), in addition to BSI secondary to indwelling catheters and infection at other sites (BSI-other). Objective: To determine the incidence, timing, risk factors, and outcomes of patients who develop MBI-LCBI in the first 100 days after HSCT. Design, Setting, and Participants: A case-cohort retrospective analysis was performed using data from the Center for International Blood and Marrow Transplant Research database on 16 875 consecutive pediatric and adult patients receiving a first allogeneic HSCT from January 1, 2009, to December 31, 2016. Patients were classified into 4 categories: MBI-LCBI (1481 [8.8%]), MBI-LCBI and BSI-other (698 [4.1%]), BSI-other only (2928 [17.4%]), and controls with no BSI (11 768 [69.7%]). Statistical analysis was performed from April 5 to July 17, 2018. Main Outcomes and Measures: Demographic characteristics and outcomes, including overall survival, chronic graft-vs-host disease, and transplant-related mortality (only for patients with malignant disease), were compared among groups. Results: Of the 16 875 patients in the study (9737 [57.7%] male; median [range] age, 47 [0.04-82] years) 13 686 (81.1%) underwent HSCT for a malignant neoplasm, and 3189 (18.9%) underwent HSCT for a nonmalignant condition. The cumulative incidence of MBI-LCBI was 13% (99% CI, 12%-13%) by day 100, and the cumulative incidence of BSI-other was 21% (99% CI, 21%-22%) by day 100. Median (range) time from transplant to first MBI-LCBI was 8 (<1 to 98) days vs 29 (<1 to 100) days for BSI-other. Multivariable analysis revealed an increased risk of MBI-LCBI with poor Karnofsky/Lansky performance status (hazard ratio [HR], 1.21 [99% CI, 1.04-1.41]), cord blood grafts (HR, 2.89 [99% CI, 1.97-4.24]), myeloablative conditioning (HR, 1.46 [99% CI, 1.19-1.78]), and posttransplant cyclophosphamide graft-vs-host disease prophylaxis (HR, 1.85 [99% CI, 1.38-2.48]). One-year mortality was significantly higher for patients with MBI-LCBI (HR, 1.81 [99% CI, 1.56-2.12]), BSI-other (HR, 1.81 [99% CI, 1.60-2.06]), and MBI-LCBI plus BSI-other (HR, 2.65 [99% CI, 2.17-3.24]) compared with controls. Infection was more commonly reported as a cause of death for patients with MBI-LCBI (139 of 740 [18.8%]), BSI (251 of 1537 [16.3%]), and MBI-LCBI plus BSI (94 of 435 [21.6%]) than for controls (566 of 4740 [11.9%]). Conclusions and Relevance: In this cohort study, MBI-LCBI, in addition to any BSIs, were associated with significant morbidity and mortality after HSCT. Further investigation into risk reduction should be a clinical and scientific priority in this patient population.


Assuntos
Bacteriemia/epidemiologia , Infecção Hospitalar/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Membrana Mucosa/lesões , Adulto , Bacteriemia/sangue , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/microbiologia , Infecção Hospitalar/microbiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/microbiologia , Estudos Retrospectivos , Fatores de Risco
8.
Ann Clin Transl Neurol ; 7(2): 169-180, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31967741

RESUMO

OBJECTIVE: In metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients. METHODS: Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age-matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t-test, linear regression or the nonparametric Mann-Whitney U-test was performed to evaluate differences between the transplanted, nontransplanted, and control group. RESULTS: In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti-inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross-correction to resident astrocytes and oligodendrocytes. INTERPRETATION: In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross-correction of oligo- and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.

9.
Biol Blood Marrow Transplant ; 26(1): 114-122, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344451

RESUMO

Development of autoimmune cytopenia (AIC) after allogeneic hematopoietic cell transplantation (HCT) is a serious complication requiring urgent intensification of immunosuppressive therapy. The pathophysiology and predictors of AIC are not completely understood. In this retrospective cohort analysis of 380 pediatric patients, we evaluated the incidence, outcomes, and related various variables, including immune reconstitution markers to AIC. Three hundred eighty patients (median age, 7.4 years; range, .1 to 22.7) were included, of which 30 patients (7.8%) developed AIC in 1 (n = 6), 2 (n = 6), or 3 (n = 16) cell lineages at a median of 133 days (range, 46 to 445) after HCT. Using multivariate analysis we found that chemo-naivety before HCT, acute graft-versus-host disease (aGVHD) grades II to IV, and serotherapy were associated with the development of AIC. Development of AIC was preceded by increased levels of IgM, IgA, and IgG. Immune profiles of total absolute lymphocytes were very similar between AIC patients and control subjects. However, CD3-CD16+CD56+ natural killer cells, CD3+ T cells, CD3+CD4+ T cell subset, and CD3+CD8+ T cell subset were lower in AIC patients. Overall survival was good, at 83% (similar between AIC patients and control subjects). In conclusion, we identified chemo-naivety before HCT, preceding aGVHD grades II to IV, and serotherapy as predictors for development of AIC. Increasing levels of IgM, IgA, and IgG preceded AIC development. These data provide clues to further study the biology of AIC.

11.
Blood Adv ; 3(17): 2525-2536, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31471322

RESUMO

Presumably, reduced-intensity/nonmyeloablative conditioning (RIC/NMA) for allogeneic hematopoietic cell transplantation (alloHCT) results in reduced infections compared with myeloablative conditioning (MAC) regimens; however, published evidence is limited. In this Center for International Blood and Marrow Transplant Research study, 1755 patients (aged ≥40 years) with acute myeloid leukemia in first complete remission were evaluated for infections occurring within 100 days after T-cell replete alloHCT. Patients receiving RIC/NMA (n = 777) compared with those receiving MAC (n = 978) were older and underwent transplantation more recently; however, the groups were similar regarding Karnofsky performance score, HCT-comorbidity index, and cytogenetic risk. One or more infections occurred in 1045 (59.5%) patients (MAC, 595 [61%]; RIC/NMA, 450 [58%]; P = .21) by day 100. The median time to initial infection after MAC conditioning occurred earlier (MAC, 15 days [range, <1-99 days]; RIC/NMA, 21 days [range, <1-100 days]; P < .001). Patients receiving MAC were more likely to experience at least 1 bacterial infection by day 100 (MAC, 46% [95% confidence interval (CI), 43-49]; RIC/NMA, 37% [95% CI, 34-41]; P = .0004), whereas at least a single viral infection was more prevalent in the RIC/NMA cohort (MAC, 34% [95% CI, 31-37]; RIC/NMA, 39% [95% CI, 36-42]; P = .046). MAC remained a risk factor for bacterial infections in multivariable analysis (relative risk, 1.44; 95% CI, 1.23-1.67; P < .0001). Moreover, the rate of any infection per patient-days at risk in the first 100 days (infection density) after alloHCT was greater for the MAC cohort (1.21; 95% CI, 1.11-1.32; P < .0001). RIC/NMA was associated with reduced infections, especially bacterial infections, in the first 100 days after alloHCT.


Assuntos
Infecções Bacterianas/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções/etiologia , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/efeitos adversos , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/complicações , Agonistas Mieloablativos/uso terapêutico , Indução de Remissão , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Resultado do Tratamento
12.
Front Med (Lausanne) ; 6: 151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31334235

RESUMO

Biomedical scientists aim to contribute to further understanding of disease pathogenesis and to develop new diagnostic and therapeutic tools that relieve disease burden. Yet the majority of biomedical scientists do not develop their academic career or professional identity as "translational scientists," and are not actively involved in the continuum from scientific concept to development of new strategies that change medical practice. The collaborative nature of translational medicine and the lengthy process of bringing innovative findings from bench to bedside conflict with established pathways of building a career in academia. This collaborative approach also poses a problem for evaluating individual contributions and progress. The traditional evaluation of scientific success measured by the impact and number of publications and grants scientists achieve is inadequate when the product is a team effort that may take decades to complete. Further, where scientists are trained to be independent thinkers and to establish unique scientific niches, translational medicine depends on combining individual insights and strengths for the greater good. Training programs that are specifically geared to prepare scientists for a career in translational medicine are not widespread. In addition, the legal, regulatory, scientific and clinical infrastructure and support required for translational research is often underdeveloped in academic institutions and funding organizations, further discouraging the development and success of translational scientists in the academic setting. In this perspective we discuss challenges and potential solutions that could allow for physicians, physician scientists and basic scientists to develop a professional identity and a fruitful career in translational medicine.

13.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.


Assuntos
Ligante de CD40/deficiência , Transplante de Células-Tronco Hematopoéticas , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Resultado do Tratamento , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/mortalidade
14.
Bone Marrow Transplant ; 54(8): 1254-1265, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30546070

RESUMO

We analyzed CIBMTR data to evaluate the incidence of non-relapse mortality (NRM) and association with overall survival (OS) for bacterial blood stream infections (BSIs) occurring within 100 days of alloHCT in 2 different phases: pre-/peri-engraftment (BSI very early phase, BSI-VEP) and BSI post-engraftment (BSI occurring between 2 weeks after engraftment and day 100, late early phase, BSI-LEP). Of the 7128 alloHCT patients, 2656 (37%) had ≥1 BSI by day 100. BSI-VEP, BSI-LEP, and BSI-Both constituted 56% (n = 1492), 31% (n = 824), and 13% (n = 340) of total BSI, respectively. Starting in 2009, we observed a gradual decline in BSI incidence through 2012 (61-48%). Patients with BSI-VEP were more likely to receive a myeloablative conditioning (MAC) regimen with total body irradiation (TBI). NRM was significantly higher in patients with any BSI (RR 1.82 95% CI 1.63-2.04 for BSI-VEP, RR 2.46, 95% CI 2.05-2.96 for BSI-LEP, and RR 2.29, 95% CI 1.87-2.81 for BSI-Both) compared with those without BSI. OS was significantly lower in patients with any BSI compared with patients without BSI (RR 1.36, 95% CI 1.26-1.47 for BSI-VEP; RR 1.83, 95% CI 1.58-2.12 for BSI-LEP: RR 1.66, 95% CI 1.43-1.94 for BSI-Both). BSIs within day 100 after alloHCT are common and remain a risk factor for mortality.


Assuntos
Bacteriemia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/métodos , Adolescente , Adulto , Bacteriemia/mortalidade , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Fatores de Risco , Adulto Jovem
15.
Biol Blood Marrow Transplant ; 25(4): 819-826, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30359735

RESUMO

Innate immune cells are the first to recover after allogeneic hematopoietic cell transplantation (HCT). Nevertheless, reports of innate immune cell recovery and their relation to adaptive recovery after HCT are largely lacking. Especially predicting CD4+ T cell reconstitution is of clinical interest, because this parameter directly associates with survival chances after HCT. We evaluated whether innate recovery relates to CD4+ T cell reconstitution probability and investigated differences between innate recovery after cord blood transplantation (CBT) and bone marrow transplantation (BMT). We developed a multivariate, combined nonlinear mixed-effects model for monocytes, neutrophils, and natural killer (NK) cell recovery after transplantation. A total of 205 patients undergoing a first HCT (76 BMT, 129 CBT) between 2007 and 2016 were included. The median age was 7.3years (range, .16 to 23). Innate recovery was highly associated with CD4+ T cell reconstitution probability (P < .001) in multivariate analysis correcting for covariates. Monocyte (P < .001), neutrophil (P < .001), and NK cell (P < .001) recovery reached higher levels during the first 200days after CBT compared with BMT. The higher innate recovery after CBT may be explained by increased proliferation capacity (measured by Ki-67 expression) of innate cells in CB grafts compared with BM grafts (P = .041) and of innate cells in vivo after CBT compared with BMT (P = .048). At an individual level, patients with increased innate recovery after either CBT or BMT had received grafts with higher proliferating innate cells (CB; P = .004, BM; P = .01, respectively). Our findings implicate the use of early innate immune monitoring to predict the chance of CD4+ T cell reconstitution after HCT, with respect to higher innate recovery after CBT compared with BMT.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunidade Inata/imunologia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Adulto Jovem
16.
J Allergy Clin Immunol ; 140(6): 1643-1650.e9, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28392330

RESUMO

BACKGROUND: Viral reactivations (VRs) after hematopoietic cell transplantation (HCT) contribute to significant morbidity and mortality. Timely immune reconstitution (IR) is suggested to prevent VR. OBJECTIVES: We studied the relation between IR (as a continuous predictor over time) and VR (as a time-varying predictor) and the relation between VR and other clinical outcomes. METHODS: In this retrospective analysis all patients receiving a first HCT between January 2004 and September 2014 were included. IR (CD3/CD4/CD8 T, natural killer, and B cells) was measured biweekly until 12 weeks and monthly thereafter. Main outcomes of interest were VR of adenovirus, EBV, human herpesvirus 6 (HHV6), cytomegalovirus (CMV), and BK virus screened weekly. Clinical outcomes included overall survival (OS), event-free-survival, nonrelapse mortality (NRM), and graft-versus-host disease. Cox proportional hazard and Fine and Gray competing risk models were used. RESULTS: Two hundred seventy-three patients (age, 0.1-22.7 years; median follow-up, 58 months) were included. Delayed CD4 reconstitution predicted reactivation of adenovirus (hazard ratio [HR], 0.995; P = .022), EBV (HR, 0.994; P = .029), and HHV6 (HR, 0.991; P = .012) but not CMV (P = .31) and BK virus (P = .27). Duration of adenovirus reactivation was shorter with timely CD4 reconstitution, which was defined as 50 × 106 cells/L or greater within 100 days. Adenovirus reactivation predicted lower OS (HR, 2.17; P = .0039) and higher NRM (HR, 2.96; P = .0008). Concomitant CD4 reconstitution abolished this negative effect of adenovirus reactivation (OS, P = .67; NRM, P = .64). EBV and HHV6 reactivations were predictors for the occurrence of graft-versus-host disease, whereas CMV and BK virus reactivation did not predict clinical outcomes. CONCLUSION: These results stress the importance of timely CD4 reconstitution. Strategies to improve CD4 reconstitution can improve HCT outcomes, including survival, and reduce the need for toxic antiviral therapies.


Assuntos
Doença Enxerto-Hospedeiro/virologia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Complicações Pós-Operatórias/virologia , Ativação Viral , Adolescente , Adulto , Criança , Pré-Escolar , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Complicações Pós-Operatórias/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
17.
Sci Transl Med ; 9(386)2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28424327

RESUMO

The molecular pathways that regulate the tissue repair function of type I interferon (IFN-I) during acute tissue damage are poorly understood. We describe a protective role for IFN-I and the RIG-I/MAVS signaling pathway during acute tissue damage in mice. Mice lacking mitochondrial antiviral-signaling protein (MAVS) were more sensitive to total body irradiation- and chemotherapy-induced intestinal barrier damage. These mice developed worse graft-versus-host disease (GVHD) in a preclinical model of allogeneic hematopoietic stem cell transplantation (allo-HSCT) than did wild-type mice. This phenotype was not associated with changes in the intestinal microbiota but was associated with reduced gut epithelial integrity. Conversely, targeted activation of the RIG-I pathway during tissue injury promoted gut barrier integrity and reduced GVHD. Recombinant IFN-I or IFN-I expression induced by RIG-I promoted growth of intestinal organoids in vitro and production of the antimicrobial peptide regenerating islet-derived protein 3 γ (RegIIIγ). Our findings were not confined to RIG-I/MAVS signaling because targeted engagement of the STING (stimulator of interferon genes) pathway also protected gut barrier function and reduced GVHD. Consistent with this, STING-deficient mice suffered worse GVHD after allo-HSCT than did wild-type mice. Overall, our data suggest that activation of either RIG-I/MAVS or STING pathways during acute intestinal tissue injury in mice resulted in IFN-I signaling that maintained gut epithelial barrier integrity and reduced GVHD severity. Targeting these pathways may help to prevent acute intestinal injury and GVHD during allogeneic transplantation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína DEAD-box 58/metabolismo , Mucosa Intestinal/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteína DEAD-box 58/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Transplante de Células-Tronco Hematopoéticas , Interferon Tipo I/metabolismo , Intestinos/efeitos da radiação , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/fisiologia , Organoides/citologia , Organoides/metabolismo , Reação em Cadeia da Polimerase , Transdução de Sinais/fisiologia , Transplante Homólogo
18.
Blood ; 128(23): 2734-2741, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27702800

RESUMO

Successful immune reconstitution (IR) is associated with improved outcomes following pediatric cord blood transplantation (CBT). Usage and timing of anti-thymocyte globulin (ATG), introduced to the conditioning to prevent graft-versus-host disease and graft failure, negatively influences T-cell IR. We studied the relationships among ATG exposure, IR, and clinical outcomes. All pediatric patients receiving a first CBT between 2004 and 2015 at the University Medical Center Utrecht were included. ATG-exposure measures were determined with a validated pharmacokinetics model. Main outcome of interest was early CD4+ IR, defined as CD4+ T-cell counts >50 × 106/L twice within 100 days after CBT. Other outcomes of interest included event-free survival (EFS). Cox proportional-hazard and Fine-Gray competing-risk models were used. A total of 137 patients, with a median age of 7.4 years (range, 0.2-22.7), were included, of whom 82% received ATG. Area under the curve (AUC) of ATG after infusion of the cord blood transplant predicted successful CD4+ IR. Adjusted probability on CD4+ IR was reduced by 26% for every 10-point increase in AUC after CBT (hazard ratio [HR], 0.974; P < .0001). The chance of EFS was higher in patients with successful CD4+ IR (HR, 0.26; P < .0001) and lower ATG exposure after CBT (HR, 1.005; P = .0071). This study stresses the importance of early CD4+ IR after CBT, which can be achieved by reducing the exposure to ATG after CBT. Individualized dosing of ATG to reach optimal exposure or, in selected patients, omission of ATG may contribute to improved outcomes in pediatric CBT.


Assuntos
Soro Antilinfocitário/administração & dosagem , Linfócitos T CD4-Positivos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Recuperação de Função Fisiológica/efeitos dos fármacos , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Aloenxertos , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
19.
Blood ; 127(20): 2427-38, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-26884374

RESUMO

Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval [CI], 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/virologia , Citomegalovirus/fisiologia , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Ativação Viral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Citomegalovirus/imunologia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/tratamento farmacológico , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia/complicações , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Recidiva , Sistema de Registros , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Adulto Jovem
20.
Nature ; 528(7583): 560-564, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26649819

RESUMO

Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.


Assuntos
Células Epiteliais/citologia , Interleucinas/imunologia , Mucosa Intestinal/citologia , Intestino Delgado/citologia , Regeneração , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Imunidade nas Mucosas , Interleucinas/deficiência , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestino Delgado/imunologia , Intestino Delgado/patologia , Camundongos , Organoides/citologia , Organoides/crescimento & desenvolvimento , Organoides/imunologia , Celulas de Paneth/citologia , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Nicho de Células-Tronco
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